Upregulation of enteric alpha-synuclein as a possible link between inflammatory bowel disease and Parkinson’s disease

• Published in: Gut Vol. 70; no. 10; pp. 2010 - 2012
• Main Authors: Derkinderen, Pascal, Noble, Wendy, Neunlist, Michel, Rolli-Derkinderen, Malvyne
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd and British Society of Gastroenterology 01.10.2021; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: alpha-Synuclein - metabolism; Axons; Biochemistry, Molecular Biology; Biopsy; Brain research; Colon; Crohn's disease; Digestive system; Enteric nervous system; Enteric Nervous System - metabolism; Ethics; Gastrointestinal tract; Genomics; Human health and pathology; Humans; Hypotheses; Hépatology and Gastroenterology; Inflammation; INFLAMMATORY BOWEL DISEASE; Inflammatory Bowel Diseases; Innervation; Intestine; Life Sciences; Movement disorders; Myenteric plexus; Neurobiology; Neurodegenerative diseases; NEUROGASTROENTEROLOGY; Neurons and Cognition; Parkinson Disease; Parkinson's disease; Pathogenesis; Pathology; Patients; PostScript; Proteins; Synuclein; Transcription; Up-Regulation; Vagus nerve; France; NEUROGASTROENTEROLOGY; INFLAMMATORY BOWEL DISEASE; alpha-synuclein; Parkinson’s disease; inflammatory bowel disease
• ISSN: 0017-5749; 1468-3288; 1468-3288
• DOI: 10.1136/gutjnl-2020-323482

In this context, they briefly discuss the possible role of alpha-synuclein, a neuronal protein which is not only expressed in both the gut and brain but that is also a key component of Parkinson’s disease pathology.2 They summarise their literature analysis by saying that ‘Expression of α-synuclein in both the gut and brain of Parkinson’s disease patients represents a possible link between Parkinson’s disease and inflammatory bowel disease. [...]the precise mechanism and role of enteric alpha-synuclein remain unknown’.1 Although we agree with the authors that the mechanisms by which gastrointestinal inflammation might influence Parkinson’s disease development or progression are still unclear, we would like to draw their attention to two recently published articles by our group in which we showed that alpha-synuclein accumulates in the colon of Crohn’s disease patients.3 4 Using biopsies and full-thickness segments of colon from Crohn’s disease subjects (n=10 and 4, respectively) and controls (n=12 and 4, respectively), we observed an increased expression of alpha-synuclein in both the submucosal and myenteric plexus in Crohn’s disease relative to controls3 (figure 1). Additional experiments performed in primary cultures of enteric neurons and using nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice allowed us to show that this upregulation was not transcriptionally regulated but instead likely resulted from a decrease in protein clearance via an Nrf2 pathway.4 In the context of Parkinson’s disease, this observation suggests that a sustained gastrointestinal inflammation might increase alpha-synuclein expression in the submucosal neurons whose terminal axons are only micrometres away from the gut lumen, thereby enabling pathological protein accumulation and propagation of abnormal proteins to the brain via the vagal innervation.5 Figure 1.